(Circulation. 2000;101:1206.)
© 2000 American Heart Association, Inc.
Cardiovascular Drugs |
Aspirin
From the Cardiology Section, Evans Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Mass.
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Introduction |
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 Top Introduction Mechanism of ActionPharmacology/PharmacokineticsAspirin in Coronary Artery...Aspirin in Cerebrovascular...Adverse EffectsComparison With Other...ConclusionsReferences |
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Salicylates, in the form of willow bark, were used as an analgesic during the time of Hippocrates, and their antipyretic effects have been recognized for more than 200 years.1 Acetylsalicylic acid, or aspirin, was introduced in the late 1890s2 and has been used to treat a variety of inflammatory conditions; however, the antiplatelet activity of this agent was not recognized until almost 70 years later.3 Recent advances in our understanding of the central role of platelets in the pathophysiology of cardiovascular disease have spurred in-depth investigations into the mechanisms of action of aspirin and the clinical utility of this agent in the treatment of common cardiovascular disorders.
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Mechanism of Action |
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Aspirin exerts its effect primarily by interfering with the biosynthesis of cyclic prostanoids, ie, thromboxane A2 (TXA2), prostacyclin, and other prostaglandins. These prostanoids are generated by the enzymatically catalyzed oxidation of arachidonic acid, which is itself derived from membrane phospholipids4 (Figure
). Arachidonic
acid is metabolized by the enzyme prostaglandin (PG)
H-synthase, which, through its cyclooxygenase (COX)
and peroxidase activities, results in the production of
PGG2 and PGH2,
respectively. PGH2 is then modified by specific
synthases, thus producing prostaglandins
D2, E2,
F2
, I2 (prostacyclin),
and TXA2, all of which mediate specific cellular
functions.
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PGH-synthase, also referred to as COX, exists in 2 isoforms that have significant homology of their amino acid sequences.5 A single amino acid substitution in the catalytic site of the enzyme confers selectivity to inhibitors of the COX isoforms.6 7 The first isoform (COX-1) is constitutively expressed in the endoplasmic reticulum of most cells (including platelets)8 and results in the synthesis of homeostatic prostaglandins responsible for normal cellular functions, including gastric mucosal protection, maintenance of renal blood flow, and regulation of platelet activation and aggregation.4 The second isoform (COX-2) is not routinely present in most mammalian cells but, rather, is rapidly inducible by inflammatory stimuli and growth factors and results in the production of prostaglandins that contribute to the inflammatory response.9 10
Aspirin imparts its primary antithrombotic effects through the
inhibition of PGH-synthase/COX by the irreversible
acetylation of a specific serine moiety (serine 530 of
COX-1 and serine 516 of COX-2)11 12 and is 
170-fold
more potent in inhibiting COX-1 than COX-2.13 In the
presence of aspirin, COX-1 is completely inactivated,
whereas COX-2 converts arachidonic acid not to
PGH2, but to
15-R-hydroxyeicosatetraenoic
acid (15-R-HETE).14 The end result is that
neither affected isoform is capable of converting
arachidonic acid to PGH2, a
necessary step in the production of prostanoids. The resultant
decreased production of prostaglandins and
TXA2 likely accounts for the therapeutic effects,
as well as the toxicities, of aspirin. From a
cardiovascular standpoint, it is principally the
antithrombotic effect of aspirin that results in its clinical utility.
Platelet production of TXA2 in
response to a variety of stimuli (including collagen, thrombin, and
ADP) results in the amplification of the platelet
aggregation response and in vasoconstriction.15 16
Conversely, vascular endothelial cell
production of prostacyclin results in inhibition of
platelet aggregation and induces vasodilation. Aspirin-induced
inhibition of TXA2 and PGI2
has opposing effects on hemostasis; however, the available data suggest
that the potentially prothrombotic effects of
PGI2 inhibition are not clinically relevant and
that the antithrombotic effects of TXA2
inhibition predominate.17 This may, in part, be a result
of the ability of vascular endothelial cells to
regenerate new COX and thus recover normal function,18
whereas COX inhibition in platelets is irreversible owing to the
limited mRNA pool and protein synthesis in these anuclear cells.
Other mechanisms for platelet inhibition by aspirin have been
proposed. For example, aspirin facilitates the inhibition of
platelet activation by neutrophils, an effect that appears to be
mediated by a nitric oxide (NO)/cGMP-dependent process,19
and inhibition of prostacyclin synthesis in endothelial
cells enhances NO production.20 In addition to its
antithrombotic effects, other mechanisms may contribute to the clinical
benefits of aspirin in the treatment of cardiovascular
disorders. Aspirin may help to decrease the progression of
atherosclerosis by protecting LDL from oxidative
modification21 and also improves
endothelial dysfunction in atherosclerotic
vessels.22 Several mechanisms have been proposed to
explain these benefits, all of which center on the potential role of
aspirin as an antioxidant. Salicylate has been shown to be an
inhibitor of the cytokine-dependent induction of
NOS-II gene expression,23 24 perhaps through a mechanism
involving nuclear factor-
B activation, an effect that would tend to
decrease the nitrosative stress that accompanies cytokine
elaboration. Aspirin can also directly scavenge hydroxyl radicals to
form the 2,3- and 2,5-dihydroxybenzoate derivatives, which themselves
serve as markers of oxidative stress25 and quench
oxy-radical flux,26 and can acetylate the
-amino groups of lysine residues in proteins,27 which
prevents their oxidation.28 This antioxidant effect on
proteins may be important in limiting both lipoprotein oxidation and
fibrinogen oxidation; in the latter case, oxidation enhances fibrin
formation,27 29 and lysine acetylation
enhances fibrinolysis.30 It is likely
through this combination of effects that aspirin reduces the
inflammatory response in patients with coronary artery
disease.31
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Pharmacology/Pharmacokinetics |
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Aspirin is rapidly absorbed in the upper gastrointestinal (GI) tract and results in a measurable inhibition of platelet function within 60 minutes.17 32 This antiplatelet effect is associated with prolongation of the bleeding time and inhibition of TXA2-dependent platelet aggregation.33 These effects occur even before acetylsalicylic acid is detectable in the peripheral blood, owing to the exposure of platelets to aspirin in the portal circulation.34 Enteric coating of aspirin significantly delays its absorption.35 The plasma half-life of aspirin is only 20 minutes; however, because platelets cannot generate new COX, the effects of aspirin last for the duration of the life of the platelet (
10 days). After a single dose of
aspirin, platelet COX activity recovers by 10% per day as a
function of platelet turnover.36 Although it may take
10 days for the total platelet population to be renewed, and thus
restore normal COX activity, it has been shown that if as little as
20% of platelets have normal COX activity, hemostasis may be
normal.37 38 The dose of aspirin required to obtain adequate platelet inhibition has been studied extensively. A single dose of 100 mg of aspirin effectively abolishes the production of TXA2 in normal individuals, as well as in patients with atherosclerotic disease.39 40 Single doses below 100 mg result in a dose-dependent effect on TXA2 production; the effect of repeated daily doses is cumulative, although >24 hours may be required to achieve maximal COX inhibition.38 39 41 Therapeutic benefit in a variety of cardiovascular diseases has been demonstrated with doses of 30 to 1500 mg/d; higher doses do not appear to be more effective but may increase the risk of GI side effects.17 42 Low-dose aspirin or controlled-release preparations may result in somewhat preferential inhibition of platelet COX over endothelial COX.33 40 43 This differential effect has theoretical advantages in that intact endothelial PGI2 production may enhance the antithrombotic effects of aspirin; however, the clinical importance of maintaining normal PGI2 production remains undetermined.
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Aspirin in Coronary Artery Disease |
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Acute Therapy
Acute Myocardial Infarction
The importance of platelets and thrombosis in the pathophysiology of acute coronary syndromes is well established. Although early studies of the use of aspirin as an antithrombotic agent in the acute treatment of myocardial infarction (MI) yielded conflicting results, the Second International Study of Infarct Survival (ISIS-2)44 has since unequivocally established the benefit of aspirin in this setting. In this trial, 17 187 patients presenting within 24 hours of the onset of a suspected acute MI (AMI) were randomized to receive intravenous streptokinase (1.5 MU), 162.5 mg of aspirin daily for 30 days, both, or neither. At the end of 5 weeks, patients receiving aspirin therapy alone had a highly significant 23% reduction in vascular mortality and a nearly 50% reduction in the risk of nonfatal reinfarction and nonfatal stroke. This benefit occurred irrespective of whether heparin was given. These reductions translate into the avoidance of
25 deaths and 10 to 15 nonfatal reinfarctions
or strokes by treating 1000 patients with aspirin for 1 month.
Additionally, there was no increase in major bleeding complications
(including no increase in cerebral hemorrhage or need for
transfusion) with aspirin therapy, and the mortality benefit was
maintained after 10 years of follow-up.45 In the past decade, thrombolytic therapy has become the cornerstone of medical management of AMI.46 47 Aspirin, however, remains an important adjunctive therapy. In ISIS-2,44 administration of streptokinase alone was associated with a 25% reduction in vascular deaths, and the effect of aspirin therapy was additive (42% reduction in vascular mortality with combined aspirin and streptokinase therapy). Additionally, an excess of nonfatal reinfarctions was seen in the first several days after treatment with streptokinase alone, likely as a result of plasmin-induced platelet activation; this increase was entirely prevented by the concomitant use of aspirin. Compared with aspirin as an adjunct to thrombolysis, heparin appears to be associated with a higher early patency rate of the infarct-related artery, although aspirin was associated with a trend toward a decreased 7-day reocclusion rate.48 The addition of heparin to aspirin does not clearly decrease mortality or reinfarction and is associated with an increase in bleeding complications.49 50 A meta-analysis of 32 trials using aspirin as adjunctive therapy to thrombolysis demonstrated significantly decreased reocclusion rates (11% versus 25%) and recurrent ischemic events (25% versus 41%) with aspirin therapy.51
Unstable Angina and Acute Non–ST-Segment–Elevation MI
Several studies have clearly demonstrated a beneficial role for
aspirin in the treatment of unstable angina (Table 1).52 53 54 55 Despite
instituting aspirin therapy at various doses (75 to 1300 mg/d) and
differing intervals after a patient’s initial presentation
(<24 hours to <8 days), these trials have consistently
demonstrated a significant decrease in the incidence of death or death
and nonfatal MI. Additionally, in the Research Group on Instability in
Coronary Artery Disease in Southeast Sweden (RISC)
trial,56 treatment with aspirin (75 mg/d) decreased the
progression to severe angina necessitating cardiac
catheterization by 40% at 3 months (10.8% versus
18.1%) and 29% at 12 months (20.8% versus 29.2%). Low-dose aspirin
(75 mg/d) has also been shown to decrease the risk of MI or death in
patients with asymptomatic ischemia on treadmill
testing after an episode of unstable angina or a non–Q-wave
MI.57 A review of 4000 patients with unstable angina
treated with aspirin or placebo demonstrated a 5% absolute risk
reduction in nonfatal stroke or MI or vascular death (9% versus
14%)42 ; this corresponds to 50 vascular events avoided
per 1000 patients treated with aspirin for 6 months.
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Aspirin has been compared with heparin as both alternative and adjunctive therapy in the setting of unstable angina. In the RISC trial,56 treatment with heparin alone provided no significant benefit for the incidence of MI and death, although the significant delay in instituting heparin therapy likely contributed to this finding (average delay 33 hours). Aspirin therapy was significantly better than heparin; however, the combination of aspirin and heparin produced the greatest benefit. Other studies have demonstrated a greater benefit of heparin over aspirin therapy55 58 59 and a potential increase in bleeding complications with combination therapy.55 In a recent meta-analysis, the addition of heparin to aspirin therapy in unstable angina and non–Q-wave MI resulted in a nonsignificant 33% decrease in the risk of MI or death compared with aspirin alone; this benefit occurred without an increase in bleeding complications.60 In addition, therapy with aspirin may prevent the early reactivation of angina observed after discontinuation of heparin therapy.61
Secondary Prevention
After MI
There have been 6 large, randomized trials that used aspirin alone
as long-term treatment after an AMI,62 63 64 65 66 67 and all but 1
of these62 demonstrated a trend toward decreased mortality
with aspirin therapy. The results of these trials and 139 others that
evaluated the long-term use of aspirin in a wide range of patients were
reviewed in a meta-analysis by the Antiplatelet Trialists
in 1994.42 This analysis comprised 100 000
patients, 70 000 of whom were considered "high-risk patients" by
virtue of a prior history of AMI, unstable angina, stable angina, prior
percutaneous or surgical coronary
revascularization, stroke, transient
ischemic attack (TIA), atrial fibrillation, valvular
heart disease, or peripheral vascular disease. Overall,
among these high-risk patients, aspirin reduced the risk of nonfatal MI
by approximately one-third, the risk of nonfatal stroke by one-third,
and the risk of vascular death by one-sixth.
Among 20 000 of these patients with a prior history of MI, aspirin
therapy decreased the risk of vascular events over an average 2-year
treatment period from 17.1% to 13.5%, corresponding to an absolute
decrease of 36 events per 1000 patients treated. Among 11 000 patients
with a prior stroke or TIA, aspirin therapy was associated with an
event rate of 18.4% compared with a rate of 22.2% in control subjects
(3-year decrease in absolute event rate of 38 events per 1000
patients). In other high-risk patients, the benefit was somewhat less
but still significant: the 1-year benefit in this group was 20
events per 1000 patients treated with aspirin.
These results clearly demonstrate a significant treatment effect of aspirin when given as secondary prevention in patients with underlying cardiovascular disease. Additionally, the results were significant in all groups irrespective of age, gender, or the presence of hypertension or diabetes. A wide range of dosing regimens was evaluated in this trial (most frequently 75 to 325 mg/d), and these regimens were equally effective. Given the effectiveness of a dose of 162.5 mg/d in the ISIS-2 trial44 and the higher incidence of GI side effects when aspirin is used chronically at higher doses (see below), it seems reasonable to begin treatment with a dose of 160 to 325 mg and continue chronic treatment with 75 to 160 mg/d in patients with coronary artery disease.
After Revascularization
Percutaneous revascularization
with balloon angioplasty or intracoronary stenting results in
local vascular trauma, with exposure of the
subendothelium to the vascular space. This highly
thrombogenic milieu predisposes to intraluminal thrombus development
with either abrupt closure or subacute thrombosis of the vessel in
3.5% to 8.6% of procedures.68 69 70 Several studies have
demonstrated a significant decrease in acute complications of
angioplasty with the combination of aspirin and
dipyridamole,71 although this combination
provides little additional benefit over aspirin alone.72
Compared with aspirin alone or a regimen of aspirin plus warfarin, the
combination of ticlopidine (500 mg/d for 1 month) and aspirin (325
mg/d) in patients undergoing intracoronary stent placement
significantly decreases the 30-day combined end point of death,
target-vessel revascularization, angiographic
thrombosis, or MI (relative risk [RR] 0.15 for combined therapy
versus aspirin alone).73 This benefit is seen irrespective
of whether the stent deployment is felt to be "successful" with a
low risk for thrombosis73 or if high-risk markers for
stent thrombosis are present.74
Coronary artery bypass surgery with saphenous vein grafts is
associated with a 5% to 15% graft occlusion rate during the first
postoperative month,75 76 which is largely related to
thrombosis at the anastomotic site as a result of
endothelial disruption and vessel
damage.77 When given in the immediate postoperative
period, aspirin clearly decreases the rate of early thrombotic graft
occlusion by 50%, and continued aspirin therapy for 1 year further
decreases the rate of occlusive events.75 76 Preoperative
administration of aspirin is associated with increased bleeding
complications but offers no additional benefit in early graft patency
compared with providing aspirin 6 hours after surgery.78
Although there does not appear to be additional benefit of aspirin with
regard to long-term graft patency after 1 year of
therapy,79 continued aspirin therapy is required for
secondary prevention of vascular events in these patients. Treatment
with ticlopidine or sulfinpyrazone also improves early graft patency;
however, these agents have not been shown to be better than
aspirin.80
Primary Prevention
In light of the benefit of aspirin in the treatment of acute
cardiovascular disease and in the secondary prevention
of recurrent events, enthusiasm has developed for the evaluation of
aspirin as a primary preventive measure (Table 2). There have been 2 large, randomized
trials of aspirin for the primary prevention of
cardiovascular events that enrolled male physicians
without prior MI and with a low incidence of prior
cardiovascular disease (eg, TIA or
angina).81 82 The Physicians’ Health Study randomized
22 071 subjects between the ages of 40 and 84 years to treatment with
aspirin (325 mg every other day) or placebo.81 The study
was stopped prematurely after an average follow-up of 5 years owing to
a highly significant 44% reduction in the risk of MI in the
aspirin-treated group (0.26% per year versus 0.44% per year), an
effect that was limited to participants over the age of 50 years.
Nonetheless, there was no decrease in cardiovascular
mortality. Additionally, there was a nonsignificant increase in
hemorrhagic stroke (RR 2.14) and a significant increase in GI bleeding
requiring transfusion. The British Physicians’ Study enrolled 5139
subjects and also demonstrated no difference in
cardiovascular mortality after 6 years of aspirin
therapy (500 mg/d).82 Importantly, this trial showed no
significant difference in the incidence of MI but a significant
increase in disabling strokes. Combined analyses of these
results demonstrated a significant 33% treatment-related reduction in
nonfatal MI but still failed to show a decrease in mortality and
demonstrated a borderline increase in hemorrhagic strokes and a
nonsignificant increase in all strokes.42 83
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These 2 trials studied a population of patients who have a very low risk for cardiovascular events. Individuals at higher risk for the development of cardiovascular events (based on their risk factor profile) were enrolled in the Thrombosis Prevention Trial84 and randomized to aspirin (75 mg/d), warfarin (average dose 4.1 mg/d), both, or neither. After >6 years of follow-up, there was a 20% reduction in ischemic heart disease events (cardiac death, fatal or nonfatal MI) in the aspirin-treated groups. This difference was almost entirely accounted for by a 32% reduction in nonfatal events, without a significant effect on mortality. In contrast, warfarin therapy resulted in a 21% reduction in ischemic events, mostly as a result of a 39% reduction in fatal events. Neither of these therapies alone resulted in an increase in the total number of strokes. The combination of aspirin and warfarin produced the greatest reduction in ischemic events (34%) but was also associated with an increase in hemorrhagic and fatal strokes.
Patients with chronic stable angina have a significant risk of developing subsequent cardiovascular events,85 and several studies have demonstrated a beneficial effect of aspirin in this group of patients. In the Physician’s Health Study, patients who had chronic stable angina and received aspirin had an 87% reduction in the risk of MI compared with their counterparts who received placebo.86 Similarly, in the Swedish Angina Pectoris Aspirin Trial, 2035 patients with chronic stable angina but without prior MI who received aspirin (75 mg/d) had a 34% decrease in the combined risk of MI and sudden death.87 The risk of stroke, however, was increased by aspirin use in both studies.
No randomized data are available regarding the use of aspirin for the primary prevention of cardiovascular disease in women. However, in a prospective cohort study of 87 678 US nurses, the use of up to 6 aspirin per week did not alter the risk of cardiovascular death, stroke, or important vascular events.88 The risk of first MI was significantly reduced (RR 0.68), although this beneficial effect was limited to women over the age of 50 years. These findings are consistent with the results of primary prevention trials in men; however, definitive recommendations await the results of the ongoing Women’s Health Study.89
In summary, the primary prevention trials demonstrate that aspirin
therapy does not decrease cardiovascular mortality but
significantly decreases the risk of nonfatal MI. There does not appear
to be a consistent effect on the incidence of stroke, although
there is a trend toward an increase in stroke risk. Additionally, there
is an increase in nonfatal bleeding. The absolute benefit of aspirin
therapy clearly increases as the risk of cardiovascular
events increases in the treatment group (Table 3). Therefore, in patients with a
relatively low risk of developing cardiovascular
disease, the risk of prophylactic aspirin therapy
may be outweighed by the risk of hemorrhagic complications. Conversely,
in patients believed to be at high risk, the benefits of therapy,
specifically a decrease in the development of MI, may outweigh the risk
of hemorrhagic complications, and prophylactic therapy may
be warranted.
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Aspirin in Cerebrovascular Disease |
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Acute Therapy
Two large, randomized trials of aspirin use in the setting of an acute, ischemic stroke have recently been reported (Table 4
).90 91 Combined, these
trials enrolled >40 000 patients within 48 hours of the onset of
neurological symptoms and demonstrated a significant decrease in the
risk of recurrent stroke and in the combined incidence of death or
nonfatal stroke (Table 4). Importantly, there was no significant
increase in hemorrhagic stroke. These results correspond to a reduction
of 10 deaths or recurrent strokes per 1000 patients after 2 to 4 weeks
of aspirin therapy. These trials also demonstrated a trend toward a
decreased incidence of death or significant disability (dependence) at
4 weeks of follow-up. The addition of heparin (5000 or 12 500 IU
subcutaneously, twice a day) to aspirin yielded no further benefit but
increased bleeding complications.90 In addition, heparin
therapy alone effected no difference in the rate of death or recurrent
stroke but resulted in a significant increase in hemorrhagic strokes
and major noncerebral bleeding.
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Secondary and Primary Prevention
There are conflicting results from individual trials regarding the
effectiveness of aspirin in the secondary prevention of cerebrovascular
events.92 93 94 95 Included in the Antiplatelet Trialists’
review were 12 randomized trials of >10 000 patients with a prior
stroke or TIA.42 Most of these patients were treated with
aspirin (50 to 1500 mg/d), although some received other
antiplatelet agents, either alone or in combination with aspirin.
Overall, there was a highly significant 17% reduction in the risk of
nonfatal stroke and of all vascular events (nonfatal stroke or MI or
vascular death) in patients treated for a mean of 33 months. This
effect was similar whether the patient presented with a TIA or
a completed stroke and resulted in a reduction of 37 vascular events
per 1000 patients treated. Similar results have been reported in 3
subsequent trials.96 97 98 In a recent meta-analysis
of 10 randomized trials comprising 9172 patients with cerebrovascular
disease who were given prolonged aspirin administration, aspirin
resulted in a significant 13% reduction in the risk of subsequent
stroke compared with placebo.99
Overall, data regarding the use of aspirin for the primary prevention
of strokes in patients at high risk are not encouraging. In the British
Physicians’ Study,82 aspirin therapy significantly
decreased the incidence of TIA (15.9% versus 27.5%;
P<0.05) but did not decrease the risk of stroke and in fact
increased the risk of disabling stroke (19.1% versus 7.4%;
P<0.05). Similarly, an increased risk of stroke, primarily
of the hemorrhagic type, was noted in the Physicians’ Health
Study.81 In a small study of asymptomatic
patients with carotid bruits and 
50% stenosis of a carotid
artery, aspirin failed to prevent subsequent cerebrovascular
events.100 Four placebo-controlled trials have evaluated
aspirin for the prevention of stroke in patients with atrial
fibrillation101 102 103 104 and, when their data are combined,
demonstrate a small but significant reduction in risk.105
However, except in the very-low-risk patient (age <65 years with no
other cardiovascular disease), the reduction in stroke
risk is much greater with warfarin therapy in trials that directly
compare the 2 agents (68% versus
12%).101 103 105 106 107
The ideal dose of aspirin for the prevention of future vascular events in patients with TIAs or minor stroke has been the subject of much debate,108 109 although several trials have demonstrated increased bleeding complications with higher doses.95 98 In the meta-analysis mentioned above, the beneficial effect of aspirin on the incidence of recurrent stroke occurred irrespective of dose (50 to 1500 mg/d).99 Additionally, in a large group of patients undergoing carotid endarterectomy, low-dose aspirin (81 or 325 mg/d) was associated with a lower risk of stroke, MI, or death compared with high-dose regimens (650 or 1300 mg/d).110 111 Thus, as is the case with coronary artery disease, a low-dose aspirin regimen appears appropriate for secondary prevention of cerebrovascular disease.
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Adverse Effects |
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The inhibition of prostaglandin synthesis is responsible for the anti-inflammatory effects of aspirin but also results in the alteration of normally protective prostaglandin functions with potentially serious consequences, including gastric ulcers, renal failure, and impaired platelet function with resultant hemorrhagic complications. These side effects and others will be discussed next.
GI Toxicity
Aspirin-induced inhibition of COX results in loss of the
cytoprotective effects of PGE2 on the gastric
mucosa. This mechanism likely accounts in part for the more frequent
development of GI side effects in the aspirin-treated patients in most
trials.93 95 97 112 Minor GI symptoms (including nausea,
vomiting, heartburn, and indigestion) have been reported in 5.2% to
40% of patients treated with aspirin versus 0.7% to 34% of patients
taking placebo,52 54 62 81 95 peptic ulcers in 0.8% to
2.6% of aspirin-treated patients versus 0% to 1.2% with
placebo,81 82 93 and major GI bleeding (melena requiring
transfusion or hematemesis) in <1% of patients in both
groups.53 81 84 87 90 Minor bleeding episodes (epistaxis,
hematuria, melena not requiring therapy, and bruising) occur frequently
in patients taking aspirin and are significantly more common than among
their placebo-treated counterparts.84 104 113 In the
United Kingdom Transient Ischaemic Attack (UK-TIA)
trial,95 the incidence of GI symptoms was not only
significantly higher in the aspirin-treated group than in the placebo
group, but GI symptoms were significantly more frequent in the
high-dose (1200 mg/d) than in the low-dose (300 mg/d) aspirin groups
(2P<0.001 for both comparisons). An overview of randomized
trials of aspirin therapy similarly found that GI toxicity (both major
and minor) was dose related with daily doses between 30 and 1300
mg.112 Nonetheless, even low doses of aspirin (50 to
75 mg/d) are not free from side effects, may still be associated with
increased GI bleeding,97 104 113 and frequently
precipitate the discontinuation of therapy.52 56
Hemorrhagic Stroke
Several studies have suggested an increase in the risk of
hemorrhagic stroke in patients treated with aspirin in the setting of
an AMI44 or acute ischemic
stroke,90 91 as well as when aspirin is used for the
primary81 or secondary97 prevention of
cardiovascular events. A recent meta-analysis
of 16 trials comprising 55 462 patients treated with aspirin or
control therapy demonstrated a significant increase in hemorrhagic
strokes (RR 1.84; P<0.001) despite a decrease in
ischemic strokes, total strokes, and MI.114
This relative risk translated into an absolute increase of 12
hemorrhagic strokes per 10 000 patients treated with aspirin.
Other Side Effects
The use of nonaspirin inhibitors of COX (nonsteroidal
anti-inflammatory drugs [NSAIDs]) may be associated with an increased
risk of renal insufficiency and worsening of hypertension control owing
to inhibition of renal vasodilatory
prostaglandins.115 116 Aspirin is a relatively
weak inhibitor of renal prostaglandin synthesis
and does not significantly affect renal function or blood pressure
control when used at the low to moderate doses suggested for the
treatment of cardiovascular disease.117
However, at high doses (1500 mg/d), aspirin can significantly reduce
renal sodium excretion in patients with heart failure.118
Aspirin has been reported to counteract the systemic
arterial vasodilatory effects and attenuate the mortality
benefit of ACE inhibition by enalapril in patients with congestive
heart failure.119 120 121 A similar loss of efficacy was not
seen in a post hoc analysis of the Captopril and
Thrombolysis Study.122 A recent review of the
literature in this regard suggests that low-dose aspirin (
100 mg/d)
has very little interaction with the effects of ACE
inhibitors, whereas higher doses may attenuate the benefit
of these agents in patients with hypertension or congestive heart
failure.123
A small percentage of people, most of whom have preexisting asthmatic disease, suffer from aspirin intolerance or sensitivity. Administration of aspirin to these persons results in the development of bronchoconstriction, rhinitis, and/or urticaria.124 The mechanism of this sensitivity is not known but likely results from the inhibition of COX and possibly from abnormal leukotriene production.125 Aspirin sensitivity can result in severe respiratory decompensation; however, most patients can be safely desensitized by the gradual administration of increasing doses of aspirin.
Making a Safer Aspirin
Attempts have been made to decrease the gastric toxicity of
aspirin by pharmacological manipulation.
Sustained-release43 and topical
formulations126 have been demonstrated to produce
relatively selective inhibition of platelet
TXA2 production with minimal effects on
vascular and gastric prostanoids and thus may have less gastrotoxicity.
Enteric-coated aspirin tablets may be less gastrotoxic as a result of
decreased gastric irritation. In a small endoscopic study of
asymptomatic patients undergoing long-term aspirin
therapy,127 gastric mucosal erosions were noted in 90% of
patients treated with regular aspirin compared with 60% of patients
receiving enteric-coated aspirin. Additionally, GI blood loss has been
shown to be less with enteric-coated aspirin than with the noncoated
formulation.128 Nonetheless, because the mechanism of
action of enteric-coated aspirin still leads to the systemic inhibition
of COX, coated aspirin is associated with significant gastric toxicity
compared with placebo127 and results in a similar risk of
upper GI bleeding compared with regular, uncoated
aspirin.129
Regular aspirin is rapidly absorbed from the acid environment of the stomach. Enteric coating of aspirin results in its release into the alkaline environment of the small bowel, where it is hydrolyzed. As a result, enteric-coated aspirin has lower bioavailability than regular aspirin.130 Nonetheless, the antiplatelet effects of full-dose (>300 mg) enteric-coated aspirin are similar to those of uncoated formulations.130 131 However, the efficacy of low-dose (<100 mg) enteric-coated preparations has not been clearly established, and it is possible that such doses may result in inadequate platelet inhibition. Thus, if coated aspirin is prescribed, larger doses may be necessary to obtain the desired antiplatelet effect.
The dissociation of the effects of the different COX enzymes (COX-1 and COX-2) has stimulated the production of agents that preferentially inhibit COX-2 and allow for the inhibition of inflammatory prostaglandins while leaving homeostatic prostaglandins relatively intact. Several new NSAIDs have been shown to have relative COX-2 selectivity132 133 134 and appear to be associated with fewer gastric side effects.7 135 136 The therapeutic antithrombotic effects and the toxic gastric effects of aspirin are both mediated through the inhibition of COX-1; therefore, dissociation of these effects is not feasible. However, coadministration of aspirin with the synthetic PGE2 analog misoprostol allows for the complete inhibition of TXA2 synthesis in platelets while maintaining gastric protection. This approach decreases the risk of gastric ulceration, erosion, and hemorrhage in dogs.137 138 Furthermore, in a randomized trial in healthy volunteers given anti-inflammatory doses of aspirin (3900 mg/d), cotreatment with 200 mg of misoprostol twice daily significantly reduced endoscopically documented gastric and duodenal mucosal injury (P<0.006).139
Other novel methods of improving the safety profile of aspirin are being developed. Animal models suggest that the intragastric administration of aspirin stimulates the release of NO, which decreases gastric acid secretion and increases cytoprotection, thus limiting gastric mucosal damage.140 Furthermore, compared with regular aspirin, the administration of NO-releasing derivatives of aspirin has no topical gastric irritating effects, does not worsen stress-induced gastric ulceration, and protects against toxic gastric injury.141 142 143 This marked improvement in gastric toxicity occurs with these agents despite the equivalent inhibition of COX and equipotent or enhanced antithrombotic activity compared with aspirin.143 The clinical safety and efficacy of these agents remain to be determined.
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Comparison With Other Antiplatelet Agents |
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TopIntroductionMechanism of ActionPharmacology/PharmacokineticsAspirin in Coronary Artery...Aspirin in Cerebrovascular...Adverse EffectsComparison With Other...ConclusionsReferences |
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Despite aspirin’s demonstrated effectiveness in treating and preventing atherosclerotic disease, it produces only partial inhibition of platelet aggregation, and therefore it is a relatively weak antiplatelet agent. Additionally, a minority of patients appear to be relatively resistant to the antiplatelet effects of aspirin, even when it is administered in large doses.144 Platelet aggregation studies have demonstrated incomplete inhibition of aggregation in 25% of patients with prior ischemic stroke who were receiving long-term aspirin therapy (minimum dose 325 mg/d).145 Some patients demonstrate improved platelet inhibition at higher aspirin doses; however, 8% of patients taking 1300 mg of aspirin per day may still be aspirin resistant.145 The mechanism of this decreased efficacy of aspirin in some patients is not well understood but may reflect the limited potency of aspirin as an inhibitor of COX-2, the expression of which has recently been demonstrated in human platelets.146
Aspirin does not completely inhibit TXA2 synthesis,41 and other non-TXA2–dependent activators of platelet aggregation (eg, thrombin, ADP, and collagen) can bypass the aspirin-inhibitory effect and result in thrombosis. Newer agents that interrupt these other pathways or interfere with the glycoprotein IIb/IIIa receptor, the final common pathway in platelet aggregation, may prove to be more effective antithrombotic agents.147 Several other antiplatelet agents have therefore been used for the treatment of thrombotic cardiovascular disease and have been compared with aspirin in randomized clinical trials.
In the Antiplatelet Trialists’ overview, several antithrombotic regimens were evaluated, including aspirin, ticlopidine, or sulfinpyrazone alone or the combination of aspirin plus dipyridamole.42 Direct and indirect comparisons of the effectiveness of these regimens demonstrated no significant difference in vascular events, although the numbers of patients enrolled in trials that directly compared agents were low.
Ticlopidine and Clopidogrel
Ticlopidine and clopidogrel are thienopyridine derivatives that
inhibit ADP-induced binding of fibrinogen to platelets, a process
necessary for platelet aggregation.148 In randomized
trials of patients with recent stroke or TIA, ticlopidine (250 mg twice
daily) has demonstrated a significant 23.3% reduction in the combined
incidence of stroke, MI, or vascular death compared with placebo
(11.3% per year versus 14.8% per year with placebo;
P=0.02),149 as well as a 21% lower risk
of stroke (10% versus 13%; P=0.024) and a 12% reduction
in the combined risk of death and nonfatal stroke (17% versus 19%;
P=0.048) compared with aspirin (650 mg twice
daily).150 However, ticlopidine therapy resulted in
severe neutropenia in 1% of patients.
The Clopidogrel versus Aspirin in Patients at Risk for Ischemic Events (CAPRIE) study compared the efficacy of aspirin (325 mg/d) with clopidogrel (75 mg/d) for reducing the combined incidence of ischemic stroke, MI, or vascular death in 19 185 patients with a recent stroke or MI or with symptomatic peripheral arterial disease.151 After an average follow-up of almost 2 years, clopidogrel demonstrated a significant 8.7% benefit over aspirin (5.32% versus 5.83%; P=0.043). Adverse events were not significantly different between the agents, and neutropenia was rare (0.1%) with clopidogrel.
Dipyridamole
Dipyridamole is a pyrimidopyrimidine derivative
that inhibits cyclic nucleotide phosphodiesterases and
blocks the uptake of adenosine, resulting in a reduction in
platelet cytosolic calcium and subsequent inhibition of
platelet activation.152 Initial studies demonstrated
no significant benefit of adding dipyridamole to
aspirin for the secondary prevention of stroke94 or
recurrent MI.153 The European Stroke Prevention-2 trial
randomized 6602 patients with prior minor stroke or TIA to treatment
with aspirin (50 mg/d), dipyridamole (400 mg/d), both,
or neither. After 2 years of follow-up, the 2 agents alone were found
to be equally effective in reducing the risk of stroke (RR reductions:
18% with aspirin, P=0.013; 16% with
dipyridamole, P=0.039) and stroke or death
combined (RR reductions: 13% with aspirin, P=0.016; 15%
with dipyridamole, P=0.015) compared with
placebo.104 Furthermore, the benefits were additive
with combination therapy (RR reductions: 37% for stroke,
P<0.001; 24% for combined end point, P<0.001).
A recent review of 15 randomized trials suggests that the addition of
dipyridamole to aspirin will reduce the risk of
vascular events by an additional 15% over the effects of aspirin
alone.99
Glycoprotein IIb/IIIa Inhibitors
Irrespective of the activating stimulus, the final common pathway
of platelet activation involves exposure and activation of
glycoprotein IIb/IIIa, the platelet fibrinogen
receptor. Inhibitors of this receptor, including monoclonal
antibodies and peptide- and nonpeptide-derived agents, have been
studied extensively in various settings. When added to standard
antiplatelet therapy with aspirin (325 mg) and
intravenous heparin in patients undergoing
percutaneous revascularization, the
monoclonal antibody c7E3 (abciximab) reduced the risk of
ischemic complications (death, nonfatal MI, unplanned
revascularization procedures, or refractory angina)
by 35% (8.3% versus 12.8% with placebo; P=0.008) in
patients undergoing high-risk angioplasty (unstable angina, evolving
AMI, or high-risk coronary morphology)154 and
by 56% (5.2% versus 11.7% with placebo; P<0.001) in
patients undergoing urgent or elective percutaneous
revascularization.155 A similar
reduction in the risk of early ischemic events was demonstrated
with tirofiban, a synthetic, nonpeptide IIb/IIIa inhibitor,
after high-risk coronary angioplasty156 and with
abciximab after intracoronary stenting.157
The benefit of platelet inhibition in patients with unstable angina has been assessed recently by monitoring troponin T release, which serves as a surrogate marker for thrombus formation. Patients with refractory unstable angina and elevated troponin T levels were shown to constitute a high-risk subgroup who particularly benefited from antiplatelet therapy with abciximab.158 When added to treatment with intravenous heparin in patients with unstable angina, treatment with intravenous eptifibatide (integrelin), a peptide IIb/IIIa inhibitor, decreased the incidence and duration of ischemic episodes noted on 24-hour ECG monitoring compared with aspirin therapy.159 In patients with unstable angina or non–Q-wave MI, the addition of tirofiban to aspirin therapy (325 mg/d) reduced the composite end point of death, MI, or refractory ischemia by 32% after 48 hours of therapy (3.8% versus 5.6% with heparin; P=0.01)160 ; however, at 30 days, the difference was no longer significant. In a group of patients with more severe unstable angina and a higher proportion of non–Q-wave MI, treatment with aspirin plus tirofiban resulted in an increase in mortality compared with a regimen of aspirin plus intravenous heparin (mortality rate of 4.6% versus 1.1% at 7 days; P=0.012).161 However, the addition of tirofiban to a regimen of aspirin plus heparin decreased the composite end point of death, MI, or refractory ischemia at 7 days by 32% (12.9% versus 17.9%; P=0.004). This benefit persisted, although to a smaller degree, at 30 days and at 6 months after treatment.
Taken together, these trials demonstrate a significant benefit of glycoprotein IIb/IIIa inhibitors when administered in addition to usual aspirin therapy in patients with unstable coronary syndromes and after percutaneous revascularization. Although initial studies were complicated by increased rates of bleeding,154 with adjusted heparin dosing, the expected bleeding rate is not different from that with standard heparin and aspirin therapy.155 160 161
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Conclusions |
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TopIntroductionMechanism of ActionPharmacology/PharmacokineticsAspirin in Coronary Artery...Aspirin in Cerebrovascular...Adverse EffectsComparison With Other...ConclusionsReferences |
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Aspirin clearly decreases mortality and reinfarction when given as short-term therapy for AMI, when given to patients with unstable angina, and when given as long-term secondary preventive therapy in a wide range of patients with established cardiovascular disease. Despite the strength of the data in this regard, studies suggest that aspirin remains underused for both the treatment of acute coronary syndromes162 163 and for secondary prevention of recurrent events.164 165 166 More than 10% of patients suffering an AMI do not receive aspirin therapy despite the absence of contraindications,162 and 20% to 50% of postinfarction patients may not be taking aspirin on an ongoing basis.164 165 The statistics are even worse in the elderly population: almost 30% of Medicare patients hospitalized for unstable angina are not treated with aspirin in the short term,163 and as many as 80% of nursing home patients with a prior history of MI may not be given aspirin.166 Nonetheless, its use in these settings should be the accepted standard unless absolute contraindications exist. The dose of aspirin should always be the lowest dose that is known to be effective (ie, 160 to 325 mg for acute treatment of cardiovascular events and 75 to 160 mg/d for primary and secondary prevention) because higher doses result in higher rates of complications. The role of aspirin in primary prevention is less clear. In patients felt to be at high risk of a future cardiac event owing to the presence of significant risk factors, prophylactic aspirin should be considered but weighed against the risk of potential complications. In patients at low risk of cardiac events, the risk of hemorrhagic complications may outweigh the benefits of therapy, and the current data do not support the use of prophylactic aspirin therapy in this setting. As newer aspirin regimens are developed that have improved safety profiles, the risk/benefit ratio may change to support the use of aspirin as primary prevention in a broader range of patients. Other antithrombotic agents, especially the glycoprotein IIb/IIIa inhibitors, which are capable of more complete platelet inhibition, are likely to play an increasingly greater role in the treatment of cardiovascular diseases; however, given its relative safety and extremely low cost, aspirin will continue to be an important agent in the treatment and prevention of cardiovascular diseases for the foreseeable future.
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Acknowledgments |
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This work was supported in part by National Institute of Health grants HL-48976, HL-53919, HL-53993, and HL-48743 and by a Merit Review Award from the US Veterans Administration.
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Footnotes |
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Reprint requests to Joseph Loscalzo, MD, PhD, Boston University School of Medicine, Whitaker Cardiovascular Institute, 715 Albany St, W-507, Boston, MA 02118.
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References |
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C. H. Hennekens, O. Sechenova, D. Hollar, and V. L. Serebruany Dose of Aspirin in the Treatment and Prevention of Cardiovascular Disease: Current and Future Directions. Journal of Cardiovascular Pharmacology and Therapeutics, September 1, 2006; 11(3): 170 - 176. [Abstract] [PDF]
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 I. Tancevski, A. Wehinger, W. Schgoer, P. Eller, S. Cuzzocrea, B. Foeger, J. R. Patsch, and A. Ritsch Aspirin regulates expression and function of scavenger receptor-BI in macrophages: studies in primary human macrophages and in mice FASEB J, July 1, 2006; 20(9): 1328 - 1335. [Abstract] [Full Text] [PDF]
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J. E. Freedman The Aspirin Resistance Controversy: Clinical Entity or Platelet Heterogeneity? Circulation, June 27, 2006; 113(25): 2865 - 2867. [Full Text] [PDF]
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 W. R Hiatt and M. J Krantz Masterclass series in peripheral arterial disease: Antiplatelet therapy for peripheral arterial disease and claudication Vascular Medicine, February 1, 2006; 11(1): 55 - 60. [Abstract] [PDF]
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J. S. Berger, M. C. Roncaglioni, F. Avanzini, I. Pangrazzi, G. Tognoni, and D. L. Brown Aspirin for the Primary Prevention of Cardiovascular Events in Women and Men: A Sex-Specific Meta-analysis of Randomized Controlled Trials JAMA, January 18, 2006; 295(3): 306 - 313. [Abstract] [Full Text] [PDF]
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 B. Aktas, M. Pozgajova, W. Bergmeier, S. Sunnarborg, S. Offermanns, D. Lee, D. D. Wagner, and B. Nieswandt Aspirin Induces Platelet Receptor Shedding via ADAM17 (TACE) J. Biol. Chem., December 2, 2005; 280(48): 39716 - 39722. [Abstract] [Full Text] [PDF]
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A. O. Maree, R. J. Curtin, M. Dooley, R. M. Conroy, P. Crean, D. Cox, and D. J. Fitzgerald Platelet Response to Low-Dose Enteric-Coated Aspirin in Patients With Stable Cardiovascular Disease J. Am. Coll. Cardiol., October 4, 2005; 46(7): 1258 - 1263. [Abstract] [Full Text] [PDF]
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P. J. Mason, A. K. Jacobs, and J. E. Freedman Aspirin Resistance and Atherothrombotic Disease J. Am. Coll. Cardiol., September 20, 2005; 46(6): 986 - 993. [Abstract] [Full Text] [PDF]
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A. T. Chan, E. L. Giovannucci, J. A. Meyerhardt, E. S. Schernhammer, G. C. Curhan, and C. S. Fuchs Long-term Use of Aspirin and Nonsteroidal Anti-inflammatory Drugs and Risk of Colorectal Cancer JAMA, August 24, 2005; 294(8): 914 - 923. [Abstract] [Full Text] [PDF]
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N. R. Cook, I-M. Lee, J. M. Gaziano, D. Gordon, P. M Ridker, J. E. Manson, C. H. Hennekens, and J. E. Buring Low-Dose Aspirin in the Primary Prevention of Cancer: The Women's Health Study: A Randomized Controlled Trial JAMA, July 6, 2005; 294(1): 47 - 55. [Abstract] [Full Text] [PDF]
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D. G. Jamieson, A. Parekh, and M. D. Ezekowitz Review of Antiplatelet Therapy in Secondary Prevention of Cerebrovascular Events: A Need for Direct Comparisons Between Antiplatelet Agents Journal of Cardiovascular Pharmacology and Therapeutics, July 1, 2005; 10(3): 153 - 161. [Abstract] [PDF]
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 J. Mikkelsson, M. Perola, and P. J. Karhunen Genetics of Platelet Glycoprotein Receptors: Risk of Thrombotic Events and Pharmacogenetic Implications Clinical and Applied Thrombosis/Hemostasis, April 1, 2005; 11(2): 113 - 125. [Abstract] [PDF]
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 K. K. Wu, J.-Y. Liou, and K. Cieslik Transcriptional Control of COX-2 via C/EBP{beta} Arterioscler Thromb Vasc Biol, April 1, 2005; 25(4): 679 - 685. [Abstract] [Full Text] [PDF]
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 M. Vinals, I. Bermudez, G. Llaverias, M. Alegret, R. M. Sanchez, M. Vazquez-Carrera, and J. C. Laguna Aspirin increases CD36, SR-BI, and ABCA1 expression in human THP-1 macrophages Cardiovasc Res, April 1, 2005; 66(1): 141 - 149. [Abstract] [Full Text] [PDF]
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 S. Sanderson, J. Emery, T. Baglin, and A.-L. Kinmonth Narrative Review: Aspirin Resistance and Its Clinical Implications Ann Intern Med, March 1, 2005; 142(5): 370 - 380. [Abstract] [Full Text] [PDF]
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 J. A Vita Polyphenols and cardiovascular disease: effects on endothelial and platelet function Am. J. Clinical Nutrition, January 1, 2005; 81(1): 292S - 297S. [Abstract] [Full Text] [PDF]
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 Y.-R. Jin, M.-R. Cho, C.-K. Ryu, J.-H. Chung, D.-Y. Yuk, J.-T. Hong, K.-S. Lee, J.-J. Lee, M.-Y. Lee, Y. Lim, et al. Antiplatelet Activity of J78 (2-Chloro-3-[2'-bromo, 4'-fluoro-phenyl]-amino-8-hydroxy-1,4-naphthoquinone), an Antithrombotic Agent, Is Mediated by Thromboxane (TX) A2 Receptor Blockade with TXA2 Synthase Inhibition and Suppression of Cytosolic Ca2+ Mobilization J. Pharmacol. Exp. Ther., January 1, 2005; 312(1): 214 - 219. [Abstract] [Full Text] [PDF]
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 I. Kriszbacher, M. Koppan, J. Bodis, H.-K. Yip, S.-S. Chen, and M.-C. Chen Aspirin for Stroke Prevention Taken in the Evening? * Response: Stroke, December 1, 2004; 35(12): 2760 - 2762. [Full Text] [PDF]
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 B. S. Wiggins and S. Spinler Antiplatelet and Antithrombin Therapy for Early Management of Acute Coronary Syndromes Journal of Pharmacy Practice, October 1, 2004; 17(5): 347 - 369. [Abstract] [PDF]
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R. A. Harrington, R. C. Becker, M. Ezekowitz, T. W. Meade, C. M. O'Connor, D. A. Vorchheimer, and G. H. Guyatt Antithrombotic Therapy for Coronary Artery Disease: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest, September 1, 2004; 126(3_suppl): 513S - 548S. [Abstract] [Full Text] [PDF]
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E. R. Cox, M. Frisse, A. Behm, and K. A. Fairman Over-the-Counter Pain Reliever and Aspirin Use Within a Sample of Long-term Cyclooxygenase 2 Users Arch Intern Med, June 14, 2004; 164(11): 1243 - 1246. [Full Text] [PDF]
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J.-M. Dogne, J. Hanson, X. de Leval, P. Kolh, V. Tchana-Sato, L. de Leval, S. Rolin, A. Ghuysen, P. Segers, B. Lambermont, et al. Pharmacological Characterization of N-tert-Butyl-N'-[2-(4'-methylphenylamino)-5-nitrobenzenesulfonyl]urea (BM-573), a Novel Thromboxane A2 Receptor Antagonist and Thromboxane Synthase Inhibitor in a Rat Model of Arterial Thrombosis and Its Effects on Bleeding Time J. Pharmacol. Exp. Ther., May 1, 2004; 309(2): 498 - 505. [Abstract] [Full Text] [PDF]
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A. T. Chan, E. L. Giovannucci, E. S. Schernhammer, G. A. Colditz, D. J. Hunter, W. C. Willett, and C. S. Fuchs A Prospective Study of Aspirin Use and the Risk for Colorectal Adenoma Ann Intern Med, February 3, 2004; 140(3): 157 - 166. [Abstract] [Full Text] [PDF]
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R. J.G. Peters, S. R. Mehta, K. A.A. Fox, F. Zhao, B. S. Lewis, S. L. Kopecky, R. Diaz, P. J. Commerford, V. Valentin, S. Yusuf, et al. Effects of Aspirin Dose When Used Alone or in Combination With Clopidogrel in Patients With Acute Coronary Syndromes: Observations From the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) Study Circulation, October 7, 2003; 108(14): 1682 - 1687. [Abstract] [Full Text] [PDF]
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C. J Knight Antiplatelet treatment in stable coronary artery disease Heart, October 1, 2003; 89(10): 1273 - 1278. [Full Text] [PDF]
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L. Macchi, L. Christiaens, S. Brabant, N. Sorel, S. Ragot, J. Allal, G. Mauco, and A. Brizard Resistance in vitro to low-dose aspirin is associated with platelet PlA1 (GP IIIa) polymorphism but not with C807T(GP Ia/IIa) and C-5T kozak (GP Ib{alpha}) polymorphisms J. Am. Coll. Cardiol., September 17, 2003; 42(6): 1115 - 1119. [Abstract] [Full Text] [PDF]
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 L G Hare, J V Woodside, and I S Young Dietary salicylates J. Clin. Pathol., September 1, 2003; 56(9): 649 - 650. [Full Text] [PDF]
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 C. Lenfant Clinical Research to Clinical Practice -- Lost in Translation? N. Engl. J. Med., August 28, 2003; 349(9): 868 - 874. [Full Text] [PDF]
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P. T. Martin, R. Denman, W. C. Lau, L. A. Waskell, C. J. Neer, K. Horowitz, A. S. Hopp, A. R. Tait, E. R. Bates, P. B. Watkins, et al. Atorvastatin-Clopidogrel Interaction * Response Circulation, June 24, 2003; 107 (24): e223 - e223. [Full Text] [PDF]
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P. A. Grayburn and L D. Hillis Cardiac Events in Patients Undergoing Noncardiac Surgery: Shifting the Paradigm from Noninvasive Risk Stratification to Therapy Ann Intern Med, March 18, 2003; 138(6): 506 - 511. [Abstract] [Full Text] [PDF]
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P. C. Wong, E. J. Crain, C. A. Watson, A. M. Zaspel, M. R. Wright, P. Y. Lam, D. J. P. Pinto, R. R. Wexler, and R. M. Knabb Nonpeptide Factor Xa Inhibitors III: Effects of DPC423, an Orally-Active Pyrazole Antithrombotic Agent, on Arterial Thrombosis in Rabbits J. Pharmacol. Exp. Ther., December 1, 2002; 303(3): 993 - 1000. [Abstract] [Full Text] [PDF]
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T. Cyrus, S. Sung, L. Zhao, C. D. Funk, S. Tang, and D. Pratico Effect of Low-Dose Aspirin on Vascular Inflammation, Plaque Stability, and Atherogenesis in Low-Density Lipoprotein Receptor-Deficient Mice Circulation, September 3, 2002; 106(10): 1282 - 1287. [Abstract] [Full Text] [PDF]
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A. Tiran, H.-J. Gruber, W. F. Graier, A. H. Wagner, E. B.M. van Leeuwen, and B. Tiran Aspirin Inhibits Chlamydia pneumoniae-Induced Nuclear Factor-{kappa}B Activation, Cytokine Expression, and Bacterial Development in Human Endothelial Cells Arterioscler Thromb Vasc Biol, July 1, 2002; 22(7): 1075 - 1080. [Abstract] [Full Text] [PDF]
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J.-M. Gaspoz, P. G. Coxson, P. A. Goldman, L. W. Williams, K. M. Kuntz, M.G. M. Hunink, and L. Goldman Cost Effectiveness of Aspirin, Clopidogrel, or Both for Secondary Prevention of Coronary Heart Disease N. Engl. J. Med., June 6, 2002; 346(23): 1800 - 1806. [Abstract] [Full Text] [PDF]
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R. K. Kharbanda, B. Walton, M. Allen, N. Klein, A. D. Hingorani, R. J. MacAllister, and P. Vallance Prevention of Inflammation-Induced Endothelial Dysfunction: A Novel Vasculo-Protective Action of Aspirin Circulation, June 4, 2002; 105(22): 2600 - 2604. [Abstract] [Full Text] [PDF]
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D. J. Watson, T. Rhodes, B. Cai, and H. A. Guess Lower Risk of Thromboembolic Cardiovascular Events With Naproxen Among Patients With Rheumatoid Arthritis Arch Intern Med, May 27, 2002; 162(10): 1105 - 1110. [Abstract] [Full Text] [PDF]
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 L. J. Ignarro, C. Napoli, and J. Loscalzo Nitric Oxide Donors and Cardiovascular Agents Modulating the Bioactivity of Nitric Oxide: An Overview Circ. Res., January 11, 2002; 90(1): 21 - 28. [Abstract] [Full Text] [PDF]
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J.C. Kaski Treatment of stable angina pectoris: is there a role for dipyridamole? Eur. Heart J., October 1, 2001; 22(19): 1762 - 1764. [PDF]
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S. Kamath, A.D. Blann, and G.Y.H. Lip Platelet activation: assessment and quantification Eur. Heart J., September 1, 2001; 22(17): 1561 - 1571. [PDF]
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 J. M. Alvarez, L. R. Jackson, C. Chatwin, and J. J. Smolich Low-dose postoperative aprotinin reduces mediastinal drainage and blood product use in patients undergoing primary coronary artery bypass grafting who are taking aspirin: A prospective, randomized, double-blind, placebo-controlled trial J. Thorac. Cardiovasc. Surg., September 1, 2001; 122(3): 457 - 463. [Abstract] [Full Text] [PDF]
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C.V Patil, E Nikolsky, M Boulos, E Grenadier, and R Beyar Multivessel coronary artery disease: current revascularization strategies Eur. Heart J., July 2, 2001; 22(14): 1183 - 1197. [PDF]
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 C. Napoli, G. Cirino, P. Del Soldato, R. Sorrentino, V. Sica, M. Condorelli, A. Pinto, and L. J. Ignarro Effects of nitric oxide-releasing aspirin versus aspirin on restenosis in hypercholesterolemic mice PNAS, February 27, 2001; 98(5): 2860 - 2864. [Abstract] [Full Text] [PDF]
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K. K. Wu Aspirin and Salicylate : An Old Remedy With a New Twist Circulation, October 24, 2000; 102(17): 2022 - 2023. [Full Text] [PDF]
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C. Napoli, G. Aldini, J. L. Wallace, F. de Nigris, R. Maffei, P. Abete, D. Bonaduce, G. Condorelli, F. Rengo, V. Sica, et al. Efficacy and age-related effects of nitric oxide-releasing aspirin on experimental restenosis PNAS, February 5, 2002; 99(3): 1689 - 1694. [Abstract] [Full Text] [PDF]
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J. W. Eikelboom, J. Hirsh, J. I. Weitz, M. Johnston, Q. Yi, and S. Yusuf Aspirin-Resistant Thromboxane Biosynthesis and the Risk of Myocardial Infarction, Stroke, or Cardiovascular Death in Patients at High Risk for Cardiovascular Events Circulation, April 9, 2002; 105(14): 1650 - 1655. [Abstract] [Full Text] [PDF]
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